1. Field of the Invention
The present invention relates to a process for the preparation of pure flupirtine maleate and the pure A crystal modification of flupirtine maleate.
2. Background Information
Flupirtine maleate is 2-amino-3-carbethoxyamino-6-(p-fluorobenzylamino)pyridine maleate (I). This compound is commercially available under the trade name Katadolon.RTM. and is used in particular as an analgesic.
The preparation of flupirtine maleate is described in DE 31 33 519.
2-amino-3-nitro-6-(4-fluorobenzylamino)pyridine (ANFP) is dissolved in 2-methoxyethanol and is hydrogenated with hydrogen in the presence of Raney nickel at 5 bar and 60.degree. C. to give 2,3-diamino-6-(4-fluorobenzyl-amino)pyridine. This is acylated with ethyl chloroformate and triethylamine under inert gas to give flupirtine base. The catalyst is filtered off and a solution of isopropanol and maleic acid is added directly to the filtrate which contains triethylamine hydrochloride, crude flupirtine maleate being precipitated with vigorous stirring under an inert-gas atmosphere.
Since it became known that the solvent 2-methoxyethanol used for the hydrogenation of ANFP is associated with a health risk owing to its considerable potential danger in the urogenital region, this compound is an unacceptable solvent for this reaction on the industrial scale.
During the precipitation of flupirtine maleate from the parent base, the avoidance of troublesome coloured complexes induced by atmospheric oxygen is of decisive importance. According to the colour intensity, they may very greatly impair the further purification up to on-spec flupirtine maleate.
The exclusion of atmospheric oxygen by an intensive supply of inert gas and a closed reactor system is therefore absolutely essential in this reaction step.
In a very time-consuming and inconvenient purification process, crude flupirtine maleate is converted into crude flupirtine base by liberation with ammonia or sodium hydroxide solution. The liberation process gives ammonium or sodium salts which pollute the waste water and constitute a troublesome accompanying phenomenon from the ecological point of view. The crude flupirtine base is recrystallized from isopropanol and, after clarification with activated carbon/kieselguhr, is reacted with a solution of maleic acid in isopropanol to give pure flupirtine maleate.
The complicated process used to date can be illustrated by the following reaction scheme:
A: ANFP.fwdarw.hydrogenation.fwdarw.acylation.fwdarw.crude flupirtine base I PA1 B: crude flupirtine base I.fwdarw.maleic acid.fwdarw.crude flupirtine maleate PA1 C: crude flupirtine maleate.fwdarw.liberation.fwdarw.crude flupirtine base II PA1 D: crude flupirtine base II.fwdarw.recrystallization.fwdarw.pure flupirtine base PA1 E: pure flupirtine base.fwdarw.maleic acid.fwdarw.modification.fwdarw.pure flupirtine maleate PA1 A: ANFP.fwdarw.hydrogenation.fwdarw.acylation.fwdarw.crude flupirtine base PA1 B: crude flupirtine base.fwdarw.maleic acid.fwdarw.crude flupirtine maleate PA1 C-E: not applicable PA1 F: crude maleate.fwdarw.pure maleate PA1 The dissolved and very oxygen-sensitive crude base synthesized in situ in process step A was converted by a very rapid suction filtration process into an aqueous maleic acid solution from which crude flupirtine maleate having far less colour than the earlier product is immediately precipitated with stirring. After crystallization in isopropanol-water, said crude flupirtine maleate gave an on-spec pure maleate in about 85% yield. PA1 This dramatic shortening of the preparation process for flupirtine maleate in comparison with the processes practised to date, with bypassing of the process steps C-E, makes it possible to obtain the pure maleate directly from the crude flupirtine maleate and to eliminate the troublesome colour problems in the flupirtine preparation at an early stage. PA1 A: ANFP.fwdarw.hydrogenation.fwdarw.acylation.fwdarw.crude flupirtine base PA1 B: flupirtine base.fwdarw.maleic acid.fwdarw.crude flupirtine maleate PA1 C-F: not applicable PA1 G: without isolation of the crude maleate.fwdarw.pure maleate PA1 As compared with process step F, process step G represents a substantially shorter alternative process in which the precipitation of crude flupirtine maleate from the flupirtine base formed in situ in isopropanol is effected by filtration with suction into an aqueous maleic acid solution at 50-60.degree. C. and, after crystal modification, colourless pure flupirtine maleate is obtained in 85-90% yield. PA1 A: ANFP.fwdarw.hydrogenation.fwdarw.acylation.fwdarw.crude flupirtine base (isolated) PA1 B: pure flupirtine base.fwdarw.maleic acid.fwdarw.pure flupirtine maleate PA1 Here, after acylation is complete, the flupirtine base is precipitated preferably in ethanol or water and is purified by simple recrystallization. The preparation of the pure flupirtine maleate is then carried out analogously to the process variants mentioned.
where reaction steps C-E are required purification steps without which pure, uniform and on-spec pure maleate could not be obtained. They are very labour-intensive and expensive purification operations, considerably lengthen the synthesis process and lead to an on-spec pure flupirtine maleate only by a complicated and inconvenient route which is very expensive in terms of production technology.
The extremely large reactor volumes which are required for the crystallization of the flupirtine base and for the precipitation of the flupirtine maleate and tie up a considerable amount of production capacity are considered a further criterion indicating a very high level of technical complexity in the purification steps C and E.
By metric ton of flupirtine maleate, 25 t of waste solution which contain 2-methoxyethanol, isopropanol, ammonia, ammonium maleate and water must be disposed of by incineration.
This procedure is very uneconomical and difficult to handle and furthermore does not meet the requirements for environmentally acceptable production.
The flupirtine maleate is generally obtained as a mixture of 2 crystal modifications A and B, these being present in the mixture in different ratios.
Such mixtures present a major problem with regard to further pharmaceutical processing. In particular, this has an adverse effect with regard to maintaining constant pharmaceutical production conditions and hence with respect to guaranteeing the pharmaceutical quality of an active ingredient. These different mixtures of crystal modifications lead to different release rates during release from the pharmaceutical formulation in the human body. This deficiency may delay the onset of action of flupirtine maleate as the active ingredient and hence falsify the activity balance.